Tetrazole derivatives as TRPA1 inhibitors

ABSTRACT

The present disclosure provides certain tetrazole derivatives that are inhibitors of transient receptor potential ankyrin 1 (TRPA1), and are therefore useful for the treatment of diseases treatable by inhibition of TRPA1. Also provided are pharmaceutical compositions containing the same, and processes for preparing the same.

FIELD OF THE INVENTION

The present disclosure provides certain tetrazole derivatives that areinhibitors of transient receptor potential ankyrin 1 (TRPA1), and aretherefore useful for the treatment of diseases treatable by inhibitionof TRPA1. Also provided are pharmaceutical compositions containing thesame, and processes for preparing said compounds.

BACKGROUND INFORMATION

Transient receptor potential channels (TRP channels) are a group ofvoltage-gated ion channels located mostly on the plasma membrane ofnumerous mammalian cell types. There are approximately 30 structurallyrelated TRP channels sorted into groups: TRPA, TRPC, TRPM, TRPML, TRPN,TRPP and TRPV. Transient receptor potential cation channel, subfamily A,member 1 (TRPA1), also known as transient receptor potential ankyrin 1,is the only member of the TRPA gene subfamily. Structurally, TRPAchannels are characterized by multiple N-terminal ankyrin repeats (˜14in the N-terminus of human TRPA1) that gives rise to the “A” for ankyrindesignation (Montell, 2005). TRPA1 is highly expressed in the plasmamembrane of sensory neurons in the dorsal root and nodose ganglia thatserve both skin and lung, as well as in small intestine, colon,pancreas, skeletal muscle, heart, brain, bladder and lymphocytes(https://www.proteinatlas.org/) as well as in human lung fibroblasts.

TRPA1 is best known as a sensor for environmental irritants giving riseto somatosensory modalities such as pain, cold and itch. TRPA1 isactivated by a number of reactive, electrophilic stimuli (e.g. allylisothiocyanate, reactive oxygen species), as well as non-reactivecompounds (e.g. icilin), implicated in cough associated with asthma,chronic pulmonary obstructive disease (COPD), idiopathic pulmonaryfibrosis (IPF) or post-viral cough or for chronic idiopathic cough aswell as cough in sensitive patients. (Song and Chang, 2015; Grace andBelvisi, 2011). TRPA1 inhibitors are useful in the treatment of IPF inwhich cough is highly prevalent because of the link between cough andlung injury, based on studies showing cough-induced elevation of TGF-β(Xie et al., 2009; Froese et al., 2016; Tschumperlin et al., 2003;Yamamoto et al., 2002; Ahamed et al., 2008). TRPA1 antagonists inhibitcalcium signaling triggered by cough triggers such as cigarette smokeextract (CSE) oxidative stress, inflammatory mediator release anddownregulated antioxidant gene expression (Lin et al., 2015; Wang etal., 2019). TRPA1 antagonists are effective in studies of atopicdermatitis (Oh et al., 2013; Wilson et al., 2013), contact dermatitis(Liu et al., 2013), psoriasis-associated itch (Wilson et al., 2013) andIL-31-dependent itch (Cevikbas et al., 2014). A human TRPA1gain-of-function has been associated with familial episodic painsyndrome (Kremeyer et al., 2010). A TRPA1 antagonist was effective in abehavioral model of migraine-related allodynia (Edelmayer et al., 2012).TRPA1 is selectively increased in trigeminal ganglia innervating injuredteeth when compared to TRPA1 expression in trigeminal gangliainnervating healthy teeth (Haas et al., 2011). Several anaesthetics areknown to be TRPA1 agonists, including isoflurane (Matta et al., 2008)providing rationale for TRPA1 inhibitors for the relief of post-surgicalpain. TRPA1 knockout mice and wild type mice treated with a TRPA1antagonist showed anxiolytic- and antidepressant-like phenotypes (deMoura et al., 2014). TRPA1 inhibitors are expected to have benefit inthe treatment of diabetic neuropathy based on studies showing amechanistic link of inverse regulation between AMPK and TRPA1 (Hiyama etal., 2018; Koivisto and Pertovaara, 2013; Wang et al., 2018). TRPA1knockout mice exhibit smaller myocardial infarct sizes compared to wildtype mice (Conklin et al., 2019). TRPA1 knockout and pharmacologicalintervention inhibited TNBS-induced colitis in mice (Engel et al.,2011). In a mouse brain ischaemia model, TRPA1 knock-out and TRPA1antagonists reduce myelin damage (Hamilton et al., 2016). Urate crystalsand joint inflammation are reduced in TRPA1 knockout mice in amonosodium urate mouse model of gout (Moilanen et al., 2015). TRPA1deletion in rats ameliorated joint inflammation and hyperalgesia in arat model of acute gout flares (Trevisan et al., 2014). Activation ofTRPA1 elicits an inflammatory response in osteoarthritic chondrocytes(Nummenmaa et al., 2016). TRPA1 inhibition and genetic deletion reducesinflammatory mediators in osteoarthritic mouse chondrocytes and murinecartilage (Nummenmaa et al., 2016). Finally, TRPA1 knockout miceexhibited improvements in weight bearing on the osteoarthritic limb inan MIA-evoked knee swelling model (Horvath et al., 2016). TRPA1 isdifferentially expressed in the bladder epithelium of rats (Du et al.,2007) and of patients with bladder outlet obstruction (Du et al., 2008).TRPA1 receptor modulation attenuates bladder overactivity in a rat modelof spinal cord injury (Andrade et al., 2011) and intrathecaladministration of TRPA1 antagonists attenuate cyclophosphamide-inducedcystitis in rats with hyper-reflexia micturition (Chen et al., 2016).

It is therefore desirable to provide potent TRPA1 inhibitors.

TRPA1 inhibitors of various structural classes are reviewed in S.Skerratt, Progress in Medicinal Chemistry, 2017, Volume 56, 81-115, inD. Preti, G. Saponaro, A. Szallasi, Pharm. Pat. Anal. (2015) 4 (2),75-94, and in H. Chen, Transient receptor potential ankyrin 1 (TRPA1)antagonists: a patent review (2015-2019), Expert Opin Ther Pat., 2020.

WO2017/060488 discloses compounds that are antagonists of TRPA1, havingthe generalized structural formula

The TRPA1 activity of Examples 28 and 29 bearing a tetrazolyl ringtherein is not disclosed.

L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809 disclosesquinazolinone-based TRPA1 antagonists including compounds of thegeneralized structural formula

of which compound 31, wherein R is OH, is disclosed as having anantagonistic TRPA1 activity of IC₅₀ 58 nM in a FLIPR assay and having anintrinsic clearance in human liver microsomes of <14 μL/min/kg.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses novel tetrazole derivatives that areinhibitors of transient receptor potential ankyrin 1 (TRPA1), possessingappropriate pharmacological and pharmacokinetic properties enablingtheir use as medicaments for the treatment of conditions and/or diseasestreatable by inhibition of TRPA1.

The compounds of the present invention may provide several advantages,such as enhanced potency, high metabolic and/or chemical stability, highselectivity, safety and tolerability, enhanced solubility, enhancedpermeability, desirable plasma protein binding, enhancedbioavailability, suitable pharmacokinetic profiles, and the possibilityto form stable salts.

The Compounds of the Invention

The present invention provides novel tetrazole derivatives that aresurprisingly potent inhibitors of TRPA1 (Assay A), further characterisedby

-   -   improved stability in human liver microsomes (Assay B)    -   improved stability in human hepatocytes (Assay C)

Compounds of the present invention differ structurally from examples 28and 29 in WO2017/060488 in their thieno[2,3-d]pyrimidinone core as wellas substituents adjacent to a secondary aliphatic alcohol. Compounds ofthe present invention additionally differ structurally from example 31in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809, in that theybear a tetrazolyl ring. These structural differences unexpectedly leadto a favourable combination of (i) inhibition of TRPA1, (ii) stabilityin human liver microsomes, and (iii) stability in human hepatocytes.

Compounds of the invention are thus superior to those disclosed in theprior art in terms of the combination of the following parameters:

-   -   potency as inhibitors of TRPA1    -   stability in human liver microsomes    -   stability in human hepatocytes

Stability in human liver microsomes refers to the susceptibility ofcompounds to biotransformation in the context of selecting and/ordesigning drugs with favorable pharmacokinetic properties as a firstscreening step. The primary site of metabolism for many drugs is theliver. Human liver microsomes contain the cytochrome P450s (CYPs), andthus represent a model system for studying phase I drug metabolism invitro Enhanced stability in human liver microsomes is associated withseveral advantages, including increased bioavailability and adequatehalf-life, which can enable lower and less frequent dosing of patients.Thus, enhanced stability in human liver microsomes is a favorablecharacteristic for compounds that are to be used for drugs. Therefore,compounds of the present invention in addition to being able to inhibitTRPA1 are expected to have a favorable in vivo clearance and thus thedesired duration of action in humans.

Stability in human hepatocytes refers to the susceptibility of compoundsto biotransformation in the context of selecting and/or designing drugswith favorable pharmacokinetic properties. The primary site ofmetabolism for many drugs is the liver. Human hepatocytes contain thecytochrome P450s (CYPs) and other drug metabolizing enzymes, and thusrepresent a model system for studying drug metabolism in vitro.(Importantly, in contrast to liver microsomes assay, the hepatocytesassay covers also phase II biotransformations as well as liver-specifictransporter-mediated processes, and therefore represents a more completesystem for drug metabolism studies). Enhanced stability in humanhepatocytes is associated with several advantages, including increasedbioavailability and adequate half-life, which can enable lower and lessfrequent dosing of patients. Thus, enhanced stability in humanhepatocytes is a favorable characteristic for compounds that are to beused for drugs.

The present invention provides novel compounds according to formula (I)

whereinA is selected from the group consisting of phenyl, thienophenyl,benzothiophenyl and benzofuranyl, unsubstituted or substituted with oneor two members of the group R¹ consisting of —CN, halogen, C₁₋₄-alkyl,C₁₋₄-fluoroalkyl, O—C₁₋₄-fluoroalkyl, C₃₋₄-cycloalkyl,O—C₃₋₄-cycloalkyl, C₃₋₄-cyclofluoroalkyl and O—C₃₋₄-cyclofluoroalkyl.

Another embodiment of the present invention relates to a compound offormula (I), wherein A is selected from the group consisting of phenyl,thienophenyl, benzothiophenyl and benzofuranyl, unsubstituted orsubstituted with one or two members of the group R¹ selected from H₃C—O,NC—, Br, Cl, F and H₃C.

Another embodiment of the present invention relates to a compound offormula (I), wherein

A is selected from the group consisting of

unsubstituted or substituted with one or two members of the group R¹,wherein R¹ is defined as in any of the preceding embodiments.

Another embodiment of the present invention relates to a compound offormula (I), wherein

A is selected from the group consisting of

Particularly preferred is the compound according to formula (I) selectedfrom the group consisting of

Used Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In generalin groups like HO, H₂N, (O)S, (O)₂S, NC (cyano), HOOC, F₃C or the like,the skilled artisan can see the radical attachment point(s) to themolecule from the free valences of the group itself. For combined groupscomprising two or more subgroups, the last named subgroup is the radicalattachment point, for example, the substituent “aryl-C₁₋₃-alkyl” meansan aryl group which is bound to a C₁₋₃-alkyl-group, the latter of whichis bound to the core or to the group to which the substituent isattached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk may be used in sub-formulas to indicate thebond which is connected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom thatis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond that isconnected to the core molecule as defined.

The term “C_(1-n)-alkyl”, wherein n is an integer selected from 2, 3, 4or 5, either alone or in combination with another radical denotes anacyclic, saturated, branched or linear hydrocarbon radical with 1 to n Catoms. For example the term C₁₋₅-alkyl embraces the radicals H₃C—,H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—,H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “fluoro” added to an “alkyl”, “alkylene” or “cycloalkyl” group(saturated or unsaturated) means such a alkyl or cycloalkyl groupwherein one or more hydrogen atoms are replaced by a fluorine atom.Examples include, but are not limited to: H₂FC—, HF₂C— and F₃C—.

The term phenyl refers to the radical of the following ring

The term thiophenyl refers to the radical of the following ring

The term benzothiophenyl refers to the radical of the following ring

The term benzofuranyl refers to the radical of the following ring

The term thieno[2,3-d]pyrimidinone refers to the radical of thefollowing ring

The term tetrazole refers to the radical of the following ring

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

In general, substantially pure stereoisomers can be obtained accordingto synthetic principles known to a person skilled in the field, e.g. byseparation of corresponding mixtures, by using stereochemically purestarting materials and/or by stereoselective synthesis. It is known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, e.g. starting from optically activestarting materials and/or by using chiral reagents.

Enantiomerically pure compounds of this invention or intermediates maybe prepared via asymmetric synthesis, for example by preparation andsubsequent separation of appropriate diastereomeric compounds orintermediates which can be separated by known methods (e.g. bychromatographic separation or crystallization) and/or by using chiralreagents, such as chiral starting materials, chiral catalysts or chiralauxiliaries.

Further, it is known to the person skilled in the art how to prepareenantiomerically pure compounds from the corresponding racemic mixtures,such as by chromatographic separation of the corresponding racemicmixtures on chiral stationary phases; or by resolution of a racemicmixture using an appropriate resolving agent, e.g. by means ofdiastereomeric salt formation of the racemic compound with opticallyactive acids or bases, subsequent resolution of the salts and release ofthe desired compound from the salt; or by derivatization of thecorresponding racemic compounds with optically active chiral auxiliaryreagents, subsequent diastereomer separation and removal of the chiralauxiliary group; or by kinetic resolution of a racemate (e.g. byenzymatic resolution); by enantioselective crystallization from aconglomerate of enantiomorphous crystals under suitable conditions; orby (fractional) crystallization from a suitable solvent in the presenceof an optically active chiral auxiliary.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, and commensurate with a reasonable benefit/risk ratio. Asused herein, “pharmaceutically acceptable salt” refers to derivatives ofthe disclosed compounds wherein the parent compound forms a salt or acomplex with an acid or a base. Examples of acids forming apharmaceutically acceptable salt with a parent compound containing abasic moiety include mineral or organic acids such as benzenesulfonicacid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid,gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malicacid, malonic acid, mandelic acid, methanesulfonic acid,4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinicacid, sulfuric acid and tartaric acid.

Examples for cations and bases forming a pharmaceutically acceptablesalt with a parent compound containing an acidic moiety include Na⁺, K⁺,Ca²⁺, Mg²⁺, NH₄ ⁺, L-arginine, 2,2′-iminobisethanol, L-lysine,N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoroacetate salts,) also comprise a part of the presentinvention.

Biological Assays Evaluation of TRPA1 Activity

Assay A: TRPA1 Assay

The activity of the compounds of the invention may be demonstrated usingthe following in vitro TRPA1 cell assay:

Method:

A human HEK293 cell line over-expressing the human TRPA1 ion channel(Perkin Elmer, Product No. AX-004-PCL) is used as a test system forcompound efficacy and potency. Compound activity is determined bymeasuring the effect of compounds on intracellular calcium concentrationinduced by AITC (Allylisothiocyanat) agonism in a FLIPRtetra system(Molecular Devices).

Cell Culture:

The cells are obtained as frozen cells in cryo-vials and stored untiluse at −150° C. Cells are grown in culture medium (MEM/EBSS medium with10% FCS and 0.4 mg/ML Geneticin). It is important that density does notexceed 90% confluence. For sub-culturing cells are detached from flasksby Versene. At the day before the assay, cells are detached, washedtwice with medium (MEM/EBSS medium with 10% FCS) and 20000 cells in 20μl/well are seeded to Poly D-Lysin biocoated 384-well plates (black,clear bottom, Cat. 356697) from Corning. Plates are incubated for 24hours at 37° C./5% CO2 before use in the assay.

Compound Preparation

The test compounds are dissolved in 100% DMSO at a concentration of 10mM and in a first step diluted in DMSO to a concentration of 5 mM,followed by serial dilution steps in 100% DMSO. Dilution factor andnumber of dilution steps may vary according to needs. Typically 8different concentrations by 1:5 dilutions are prepared, furtherintermediate dilutions (1:20) of the substances are carried out withHBSS/HEPES buffer (1×HEPES, Cat. 14065 from Gibco, 20 mM HEPES, Cat.83264 from SIGMA, 0.1% BSA Cat. 11926 from Invitrogen, pH 7.4

FLIPR Assay:

At the assay day cells are washed 3× with assay puffer, 20 μL bufferremaining in the wells after washing. 10 μL Ca6 kit (Cat. R8191Molecular Devices) loading buffer in HBSS/HEPES is added to the cellsand the plates are incubated with lid for 120 minutes at 37°/5% CO2. 10μL of compound or controls in HBSS/HEPES buffer/5% DMSO from theintermediate dilution plate are carefully added to the wellsLuminescence (indicating the calcium influx or release) is read on theFLIPRtetra device for 10 minutes to monitor the compound induced effects(e.g. agonism). Finally 10 μL of the agonist AITC 50 μM dissolved inHBSS/HEPES buffer/0.05% DMSO (final concentration 10 μM) is added to thewells followed by an additional read on the FLIPRtetra device for 10minutes. The area under the signal curve (AUC) after AITC addition isused for IC50/% inhibition calculations

Data Evaluation and Calculation:

Each assay microtiter plate contains wells with vehicle (1% DMSO)controls instead of compound as controls for AITC induced luminescence(100% CTL; high controls) and wells with vehicle controls without AITCas controls for non-specific changes in luminescence (0% CTL; lowcontrols).

The analysis of the data is performed by the calculation of the areaunder signal curve of the individual wells. Based on this values the %value for the measurement of each substance concentration is calculated(AUC(sample)−AUC(low))*100/(AUC(high)−AUC(low)) using MegaLab software(in house development). The IC50 values are calculated from the %control values using MegaLab software. Calculation:[y=(a−d)/(1+(x/c){circumflex over ( )}b)+d], a=low value, d=high value;x=conc M; c=IC50 M; b=hill; y=% ctrl

TABLE 1 Biological data for compounds of the invention as obtained inAssay A hTRPA1 IC₅₀ Example [nM] 1 28 2 9 3 12 4 12 5 13 6 22 7 23 8 269 29 10 31 11 31 12 34 13 37 14 41 15 65 16 70 17 131 18 143

TABLE 2 Biological data for prior art compounds (examples 28 and 29 inWO2017/060488) as obtained in Assay A. Example in hTRPA1 IC₅₀WO2017/060488 [nM] 28 366 29 1120

TABLE 3 Biological data for prior art compounds (example 31 in L.Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained inAssay A. Example in Med. Chem. hTRPA1 IC₅₀ 2016, 59, 2794-2809 [nM] 3152

Evaluation of Microsomal Clearance

Assay B: Microsomal Clearance:

The metabolic degradation of the test compound is assayed at 37° C. withpooled liver microsomes. The final incubation volume of 100 μl per timepoint contains TRIS buffer pH 7.6 at RT (0.1 M), magnesium chloride (5mM), microsomal protein (1 mg/ml) and the test compound at a finalconcentration of 1 μM.

Following a short preincubation period at 37° C., the reactions areinitiated by addition of beta-nicotinamide adenine dinucleotidephosphate, reduced form (NADPH, 1 mM) and terminated by transferring analiquot into solvent after different time points (0, 5, 15, 30, 60 min).Additionally, the NADPH-independent degradation is monitored inincubations without NADPH, terminated at the last time point. The [%]remaining test compound after NADPH independent incubation is reflectedby the parameter c(control) (metabolic stability). The quenchedincubations are pelleted by centrifugation (10000 g, 5 min). An aliquotof the supernatant is assayed by LC-MS/MS for the amount of parentcompound. The half-life (t½ INVITRO) is determined by the slope of thesemilogarithmic plot of the concentration-time profile.

The intrinsic clearance (CL_INTRINSIC) is calculated by considering theamount of protein in the incubation:CL_INTRINSIC [μl/min/mg protein]=(Ln 2/(half-life [min]*protein content[mg/ml]))*1000CL_INTRINSIC_INVIVO [ml/min/kg]=(CL_INTRINSIC [μL/min/mg protein]×MPPGL[mg protein/g liver]×liver factor [g/kg bodyweight])/1000Qh[%]=CL[ml/min/kg]/hepatic blood flow [ml/min/kg])

Hepatocellularity, human: 120×10e6 cells/g liver

Liver factor, human: 25.7 g/kg bodyweight

Blood flow, human: 21 ml/(min×kg)

TABLE 4 Biological data for compounds of the invention as obtained inAssay B Example human LM [% Qh] 1 <23 2 33 3 27 4 <23 5 28 6 <23 7 34 826 9 <23 10 <23 11 <23 12 <23 13 <23 14 <23 15 <23 16 <23 17 <23 18 <23

TABLE 5 Biological data for prior art compounds (examples 28 and 29 inWO2017/060488) as obtained in Assay B. Example in human LM WO2017/060488[% Qh] 28 62 29 <23

TABLE 6 Biological data for prior art compounds (example 31 in L.Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained inAssay B. Example in Med. Chem. human LM 2016, 59, 2794-2809 [% Qh] 31<23

Evaluation of Hepatocyte Clearance

Assay C: Hepatocyte Clearance

The metabolic degradation of the test compound is assayed in ahepatocyte suspension. Hepatocytes (cryopreserved) are incubated inDulbecco's modified eagle medium (supplemented with 3.5 μg glucagon/500mL, 2.5 mg insulin/500 mL and 3.75 mg/500 mL hydrocortison) containing5% species serum.

Following a 30 min preincubation in an incubator (37° C., 10% CO2) 5 μlof test compound solution (80 μM; from 2 mM in DMSO stock solutiondiluted 1:25 with medium) are added into 395 μl hepatocyte suspension(cell density in the range 0.25-5 Mio cells/mL depending on the species,typically 1 Mio cells/mL; final concentration of test compound 1 μM,final DMSO concentration 0.05%).

The cells are incubated for six hours (incubator, orbital shaker) andsamples (25 μl) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples aretransferred into acetonitrile and pelleted by centrifugation (5 min).The supernatant is transferred to a new 96-deepwell plate, evaporatedunder nitrogen and resuspended.

Decline of Parent Compound is Analyzed by HPLC-MS/MS

CLint is calculated as followsCL_INTRINSIC=Dose/AUC=(CO/CD)/(AUD+clast/k)×1000/60. C0: initialconcentration in the incubation [μM], CD: cell density of vital cells[10e6 cells/mL], AUD: area under the data [μM×h], clast: concentrationof last data point [μM], k: slope of the regression line for parentdecline [h−1].

The calculated in vitro hepatic intrinsic clearance can be scaled up tothe intrinsic in vivo hepatic Clearance and used to predict hepatic invivo blood clearance (CL) by the use of a liver model (well stirredmodel).CL_INTRINSIC_INVIVO [ml/min/kg]=(CL_INTRINSIC [μL/min/10e6cells]×hepatocellularity [10e6 cells/g liver]×liver factor [g/kgbodyweight])/1000CL[ml/min/kg]=CL_INTRINSIC_INVIVO [ml/min/kg]×hepatic blood flow[ml/min/kg]/(CL_INTRINSIC_INVIVO [ml/min/kg]+hepatic blood flow[ml/min/kg])Qh[%]=CL[ml/min/kg]/hepatic blood flow [ml/min/kg])

Hepatocellularity, human: 120×10e6 cells/g liver

Liver factor, human: 25.7 g/kg bodyweight

Blood flow, human: 21 ml/(min×kg)

TABLE 7 Biological data for compounds of the invention as obtained inAssay C human Hepatocytes Example [% Qh] 1 <4 2 19 3 26 4 6 5 20 6 26 741 8 20 9 14 10 8 11 14 12 <4 13 10 14 14 15 30 16 19 17 18 18 <4

TABLE 8 Biological data for prior art compounds (examples 28 and 29 inWO2017/060488) as obtained in Assay C. Example in human HepatocytesWO2017/060488 [% Qh] 28 49 29 22

TABLE 9 Biological data for prior art compounds (example 31 in L.Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained inAssay C. Example in Med. Chem. human Hepatocytes 2016, 59, 2794-2809 [%Qh] 31 73

Evaluation of Permeability

Caco-2 cells (1-2×105 cells/1 cm2 area) are seeded on filter inserts(Costar transwell polycarbonate or PET filters, 0.4 μm pore size) andcultured (DMEM) for 10 to 25 days. Compounds are dissolved inappropriate solvent (like DMSO, 1-20 mM stock solutions). Stocksolutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1mM MgSO₄, 1.8 mM CaCl₂, 4.17 mM NaHCO₃, 1.19 mM Na₂HPO₄×7H₂O, 0.41 mMNaH₂PO₄×H₂O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to preparethe transport solutions (0.1-300 μM compound, final DMSO<=0.5%). Thetransport solution (TL) is applied to the apical or basolateral donorside for measuring A-B or B-A permeability (3 filter replicates),respectively. Samples are collected at the start and end of experimentfrom the donor and at various time intervals for up to 2 hours also fromthe receiver side for concentration measurement by HPLC-MS/MS orscintillation counting. Sampled receiver volumes are replaced with freshreceiver solution.

Evaluation of Plasma Protein Binding

This equilibrium dialysis (ED) technique is used to determine theapproximate in vitro fractional binding of test compounds to plasmaproteins. Dianorm Teflon dialysis cells (micro 0.2) are used. Each cellconsists of a donor and an acceptor chamber, separated by an ultrathinsemipermeable membrane with a 5 kDa molecular weight cutoff. Stocksolutions for each test compound are prepared in DMSO at 1 mM anddiluted to a final concentration of 1.0 μM. The subsequent dialysissolutions are prepared in pooled human or rat plasma (with NaEDTA) frommale and female donors. Aliquots of 200 μL dialysis buffer (100 mMpotassium phosphate, pH 7.4) are dispensed into the buffer chamber.Aliquots of 200 μL test compound dialysis solution are dispensed intothe plasma chambers. Incubation is carried out for 2 hours underrotation at 37° C.

At the end of the dialysis period, the dialysate is transferred intoreaction tubes. The tubes for the buffer fraction contain 0.2 mLACN/water (80/20). Aliquots of 25 μL of the plasma dialysate aretransferred into deep well plates and mixed with 25 μL ACN/water(80/20), 25 μL buffer, 25 μL calibration solution and 25 μL InternalStandard solution. Protein precipitation is done by adding 200 μL ACN.Aliquots of 50 μL of the buffer dialysate are transferred into deep wellplates and mixed with 25 μL blank plasma, 25 μL Internal Standardsolution and 200 μL ACN. Samples are measured on HPLC-MS/MS-Systems andevaluated with Analyst-Software. Percent bound is calculated with theformula: % bound=(plasma concentration−buffer concentration/plasma 30concentration)×100.

Evaluation of Solubility

Saturated solutions are prepared in well plates (format depends onrobot) by adding an appropriate volume of selected aqueous media(typically in the range of 0.25-1.5 ml) into each well which contains aknown quantity of solid drug substance (typically in the range 0.5-5.0mg). The wells are shaken or stirred for a predefined time period(typically in a range of 2-24 h) and than filtered using appropriatefilter membranes (typically PTFE-filters with 0.45 μm pore size). Filterabsorption is avoided by discarding the first few drops of filtrate. Theamount of dissolved drug substance is determined by UV spectroscopy. Inaddition the pH of the aqueous saturated solution is measured using aglass-electrode pH meter.

Evaluation of Pharmacokinetic Characteristics

The test compound is administered either intravenously or orally to therespective test species. Blood samples are taken at several time pointspost application of the test compound, anticoagulated and centrifuged.

The concentration of analytes—the administered compound and/ormetabolites—are quantified in the plasma samples. PK parameters arecalculated using non compartment methods. AUC and Cmax are normalized toa dose of 1 μmol/kg.

Evaluation of Metabolism in Human Hepatocytes In Vitro

The metabolic pathway of a test compound is investigated using primaryhuman hepatocytes in suspension. After recovery from cryopreservation,human hepatocytes are incubated in Dulbecco's modified eagle mediumcontaining 5% human serum and supplemented with 3.5 μg glucagon/500 ml,2.5 mg insulin/500 ml and 3.75 mg/500 ml hydrocortisone.

Following a 30 min preincubation in a cell culture incubator (37° C.,10% CO₂), test compound solution is spiked into the hepatocytesuspension to obtain a final cell density of 1.0*10⁶ to 4.0*10⁶ cells/ml(depending on the metabolic turnover rate of the compound observed withprimary human hepatocytes), a final test compound concentration of 10μM, and a final DMSO concentration of 0.05%.

The cells are incubated for six hours in a cell culture incubator on ahorizontal shaker, and samples are removed from the incubation after 0,0.5, 1, 2, 4 or 6 hours, depending on the metabolic turnover rate.Samples are quenched with acetonitrile and pelleted by centrifugation.The supernatant is transferred to a 96-deepwell plate, evaporated undernitrogen and resuspended prior to bioanalysis by liquidchromatography-high resolution mass spectrometry for identification ofputative metabolites.

The structures are assigned tentatively based on Fourier-Transform-MS'data. Metabolites are reported as percentage of the parent in humanhepatocyte incubation with a threshold of 4%.

Method of Treatment

The present invention is directed to compounds of general formula 1which are useful in the prevention and/or treatment of a disease and/orcondition associated with or modulated by TRPA1 activity, including butnot limited to the treatment and/or prevention of fibrotic disease,inflammatory and immunoregulatory disorders, respiratory orgastrointestinal disco eases or complaints, ophthalmic diseases,inflammatory diseases of the joints and inflammatory diseases of thenasopharynx, eyes, and skin and pain and neurological disorders. Saiddisorders, diseases and complaints include cough, idiopathic pulmonaryfibrosis, other pulmonary interstitial diseases and other fibrotic,asthma or allergic diseases, eosinophilic diseases, chronic obstructivepulmonary disease, as well as inflammatory and immunoregulatorydisorders, such as rheumatoid arthritis and atherosclerosis, as well aspain and neurological disorders, such as acute pain, surgical pain,chronic pain and depression and bladder disorders.

The compounds of general formula 1 are useful for the prevention and/ortreatment of:

(1) Cough such as chronic idiopathic cough or chronic refractory cough,cough associated with asthma, COPD, lung cancer, post-viral infectionand idiopathic pulmonary fibrosis and other pulmonary interstitialdiseases.

(2) Pulmonary fibrotic diseases such as pneumonitis or interstitialpneumonitis associated with collagenosis, e.g. lupus erythematodes,systemic scleroderma, rheumatoid arthritis, polymyositis anddermatomysitis, idiopathic interstitial pneumonias, such as pulmonarylung fibrosis (IPF), non-specific interstitial pneumonia, respiratorybronchiolitis associated interstitial lung disease, desquamativeinterstitial pneumonia, cryptogenic organizing pneumonia, acuteinterstitial pneumonia and lymphocytic interstitial pneumonia, lymangisoleiomyomatosis, pulmonary alveolar proteinosis, Langerhan's cellhistiocytosis, pleural parenchymal fibroelastosis, interstitial lungdiseases of known cause, such as interstitial pneumonitis as a result ofoccupational exposures such as asbestosis, silicosis, miners lung (coaldust), farmers lung (hay and mould), Pidgeon fanciers lung (birds) orother occupational airbourne triggers such as metal dust ormycobacteria, or as a result of treatment such as radiation,methotrexate, amiodarone, nitrofurantoin or chemotherapeutics, or forgranulomatous disease, such as granulomatosis with polyangitis,Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, orinterstitial pneumonitis caused by different origins, e.g. aspiration,inhalation of toxic gases, vapors, bronchitis or pneumonitis orinterstitial pneumonitis caused by heart failure, X-rays, radiation,chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosisor mucoviscidosis, or alpha-1-antitrypsin deficiency.

(3) Other fibrotic diseases such as hepatic bridging fibrosis, livercirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis,endomyocardial fibrosis, old myocardial infarction, glial scar, arterialstiffness, arthrofibrosis, Dupuytren's contracture, keloid,scleroderma/systemic sclerosis, mediastinal fibrosis, myelofibrosis,Peyronie's disease, nephrogenic systemic fibrosis, retroperitonealfibrosis, adhesive capsulitis.

(4) Inflammatory, auto-immune or allergic diseases and conditions suchas allergic or non-allergic rhinitis or sinusitis, chronic sinusitis orrhinitis, nasal polyposis, chronic rhinosinusitis, acute rhinosinusitis,asthma, pediatric asthma, allergic bronchitis, alveolitis, hyperreactiveairways, allergic conjunctivitis, bronchiectasis, adult respiratorydistress syndrome, bronchial and pulmonary edema, bronchitis orpneumonitis, eosinophilic cellulites (e.g., Well's syndrome),eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilicpneumonia), eosinophilic fasciitis (e. g., Shulman's syndrome),delayed-type hypersensitivity, non-allergic asthma; exercise inducedbronchoconstriction; chronic obstructive pulmonary disease (COPD), acutebronchitis, chronic bronchitis, cough, pulmonary emphysema; systemicanaphylaxis or hypersensitivity responses, drug allergies (e.g., topenicillin, cephalosporin), eosinophiliamyalgia syndrome due to theingestion of contaminated tryptophane, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, Graves' disease,Sjogren's syndrome psoriatic arthritis, multiple sclerosis, systemiclupus erythematosus, myasthenia gravis, immune thrombocytopenia (adultITP, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia(auto-immune and drug induced), Evans syndrome (platelet and red cellimmune cytopaenias), Rh disease of the newborn, Goodpasture's syndrome(anti-GBM disease), Celiac, autoimmune cardio-myopathy juvenile onsetdiabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease;graft rejection (e.g., in transplantation), including allograftrejection or graftversus-host disease; inflammatory bowel diseases, suchas Crohn's disease and ulcerative colitis; spondyloarthropathies;scleroderma; psoriasis (including T-cell mediated psoriasis) andinflammatory dermatoses such as an dermatitis, eczema, atopicdermatitis, allergic contact dermatitis, urticaria; vasculitis (e. g.,necrotizing, cutaneous, and hypersensitivity vasculitis); erythemanodosum; eosinophilic myositis, eosinophilic fasciitis, cancers withleukocyte infiltration of the skin or organs; ophthalmic diseases suchas age related macular degeneration, diabetic retinopathy and diabeticmacular edema, keratitis, eosinophilic keratitis, keratoconjunctivitis,vernal keratoconjunctivitis, scarring, anterior segment scarring,blepharitis, blepharoconjunctivitis, bullous disorders, cicatricialpemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye,episcleritis, glaucoma, gliosis, Granuloma annulare, Graves'ophthalmopathy, intraocular melanoma, Pinguecula, proliferativevitreoretinopathy, pterygia, scleritis, uveitis, acute gout flares, goutor osteoarthritis.

(5) Pain such as chronic idiopathic pain syndrome, neuropathic pain,dysesthesia, allodynia, migraine, dental pain and post-surgical pain.

(6) Depression, anxiousness, diabetic neuropathy and bladder disorderssuch as bladder outlet obstruction, overactive bladder, cystitis;myocardial reperfusion injury or brain ischaemia injury.

Accordingly, the present invention relates to a compound of generalformula 1 for use as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula 1 for the treatment and/or prevention of a diseaseand/or condition associated with or modulated by TRPA1 activity.

Furthermore, the present invention relates to the use of a compound ofgeneral formula 1 for the treatment and/or prevention of fibroticdisease, inflammatory and immunoregulatory disorders, respiratory orgastrointestinal diseases or complaints, ophthalmic diseases,inflammatory diseases of the joints and inflammatory diseases of thenasopharynx, eyes, and skin, pain and neurological disorders. Saiddisorders, diseases and complaints include cough, idiopathic pulmonaryfibrosis, other pulmonary interstitial diseases and other fibrotic,asthma or allergic diseases, eosinophilic diseases, chronic obstructivepulmonary disease, as well as inflammatory and immunoregulatorydisorders, such as rheumatoid arthritis and atherosclerosis, as well aspain and neurological disorders, such as acute pain, surgical pain,chronic pain and depression and bladder disorders.

Furthermore, the present invention relates to the use of a compound ofgeneral formula 1 for the treatment and/or prevention of:

(1) Cough such as chronic idiopathic cough or chronic refractory cough,cough associated with asthma, COPD, lung cancer, post-viral infectionand idiopathic pulmonary fibrosis and other pulmonary interstitialdiseases.

(2) Pulmonary fibrotic diseases such as pneumonitis or interstitialpneumonitis associated with collagenosis, e.g. lupus erythematodes,systemic scleroderma, rheumatoid arthritis, polymyositis anddermatomysitis, idiopathic interstitial pneumonias, such as pulmonarylung fibrosis (IPF), non-specific interstitial pneumonia, respiratorybronchiolitis associated interstitial lung disease, desquamativeinterstitial pneumonia, cryptogenic organizing pneumonia, acuteinterstitial pneumonia and lymphocytic interstitial pneumonia,lymangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhan's cellhistiocytosis, pleural parenchymal fibroelastosis, interstitial lungdiseases of known cause, such as interstitial pneumonitis as a result ofoccupational exposures such as asbestosis, silicosis, miners lung (coaldust), farmers lung (hay and mould), Pidgeon fanciers lung (birds) orother occupational airbourne triggers such as metal dust ormycobacteria, or as a result of treatment such as radiation,methotrexate, amiodarone, nitrofurantoin or chemotherapeutics, or forgranulomatous disease, such as granulomatosis with polyangitis,Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, orinterstitial pneumonitis caused by different origins, e.g. aspiration,inhalation of toxic gases, vapors, bronchitis or pneumonitis orinterstitial pneumonitis caused by heart failure, X-rays, radiation,chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosisor mucoviscidosis, or alpha-1-antitrypsin deficiency.

(3) Other fibrotic diseases such as hepatic bridging fibrosis, livercirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis,endomyocardial fibrosis, old myocardial infarction, glial scar, arterialstiffness, arthrofibrosis, Dupuytren's contracture, keloid,scleroderma/systemic sclerosis, mediastinal fibrosis, myelofibrosis,Peyronie's disease, nephrogenic systemic fibrosis, retroperitonealfibrosis, adhesive capsulitis.

(4) Inflammatory, auto-immune or allergic diseases and conditions suchas allergic or non-allergic rhinitis or sinusitis, chronic sinusitis orrhinitis, nasal polyposis, chronic rhinosinusitis, acute rhinosinusitis,asthma, pediatric asthma, allergic bronchitis, alveolitis, hyperreactiveairways, allergic conjunctivitis, bronchiectasis, adult respiratorydistress syndrome, bronchial and pulmonary edema, bronchitis orpneumonitis, eosinophilic cellulites (e.g., Well's syndrome),eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilicpneumonia), eosinophilic fasciitis (e. g., Shulman's syndrome),delayed-type hypersensitivity, non-allergic asthma; exercise inducedbronchoconstriction; chronic obstructive pulmonary disease (COPD), acutebronchitis, chronic bronchitis, cough, pulmonary emphysema; systemicanaphylaxis or hypersensitivity responses, drug allergies (e.g., topenicillin, cephalosporin), eosinophiliamyalgia syndrome due to theingestion of contaminated tryptophane, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, Graves' disease,Sjogren's syndrome psoriatic arthritis, multiple sclerosis, systemiclupus erythematosus, myasthenia gravis, immune thrombocytopenia (adultITP, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia(auto-immune and drug induced), Evans syndrome (platelet and red cellimmune cytopaenias), Rh disease of the newborn, Goodpasture's syndrome(anti-GBM disease), Celiac, autoimmune cardio-myopathy juvenile onsetdiabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease;graft rejection (e.g., in transplantation), including allograftrejection or graftversus-host disease; inflammatory bowel diseases, suchas Crohn's disease and ulcerative colitis; spondyloarthropathies;scleroderma; psoriasis (including T-cell mediated psoriasis) andinflammatory dermatoses such as an dermatitis, eczema, atopicdermatitis, allergic contact dermatitis, urticaria; vasculitis (e. g.,necrotizing, cutaneous, and hypersensitivity vasculitis); erythemanodosum; eosinophilic myositis, eosinophilic fasciitis, cancers withleukocyte infiltration of the skin or organs; ophthalmic diseases suchas age related macular degeneration, diabetic retinopathy and diabeticmacular edema, keratitis, eosinophilic keratitis, keratoconjunctivitis,vernal keratoconjunctivitis, scarring, anterior segment scarring,blepharitis, blepharoconjunctivitis, bullous disorders, cicatricialpemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye,episcleritis, glaucoma, gliosis, Granuloma annulare, Graves'ophthalmopathy, intraocular melanoma, Pinguecula, proliferativevitreoretinopathy, pterygia, scleritis, uveitis, acute gout flares, goutor osteoarthritis.

(5) Pain such as chronic idiopathic pain syndrome, neuropathic pain,dysesthesia, allodynia, migraine, dental pain and post-surgical pain.

(6) Depression, anxiousness, diabetic neuropathy and bladder disorderssuch as bladder outlet obstruction, overactive bladder, cystitis;myocardial reperfusion injury or brain ischaemia injury.

In a further aspect the present invention relates to a compound ofgeneral formula 1 for use in the treatment and/or prevention of abovementioned diseases and conditions.

In a further aspect the present invention relates to the use of acompound of general formula 1 for the preparation of a medicament forthe treatment and/or prevention of above mentioned diseases andconditions.

In a further aspect of the present invention the present inventionrelates to methods for the treatment or prevention of above mentioneddiseases and conditions, which method comprises the administration of aneffective amount of a compound of general formula 1 to a human being.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with fibrotic diseases,inflammatory and immunoregulatory disorders, respiratory orgastrointestinal diseases or comas plaints, inflammatory diseases of thejoints or of the nasopharynx, eyes, and skin or conditions such as forexample cough, idiopathic pulmonary fibrosis, other pulmonaryinterstitial diseases, asthma or allergic diseases, eosinophilicdiseases, chronic obstructive pulmonary disease, atopic dermatitis aswell as autoimmune pathologies, such as rheumatoid arthritis andatherosclerosis, or therapeutic agents useful for the treatment ofophthalmic diseases, pain and depression.

Additional therapeutic agents that are suitable for such combinationsinclude in particular those, which, for example, potentiate thetherapeutic effect of one or more active substances with respect to oneof the indications mentioned and/or allow the dosage of one or moreactive substances to be reduced.

Therefore, a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofantifibrotic agents, anti-tussive agents, anti-inflammatory agents,anti-atopic dermatitis agents, analgesics, anti-convulsants,anxiolytics, sedatives, skeletal muscle relaxants or anti-depressants.

Antifibrotic agents are for example nintedanib, pirfenidone,phosphodiesterase-IV (PDE4) inhibitors such as roflumilast, autotaxininhibitors such as GLPG-1690 or BBT-877; connective tissue growth factor(CTGF) blocking antibodies such as Pamrevlumab; B-cell activating factorreceptor (BAFF-R) blocking antibodies such as Lanalumab; alpha-V/beta-6blocking inhibitors such as BG-00011/STX-100, recombinant pentraxin-2(PTX-2) such as PRM-151; c-Jun N-terminal kinase (JNK) inhibitors suchas CC-90001; galectin-3 inhibitors such as TD-139; G-protein coupledreceptor 84 (GPR84) inhibitors such as GLPG1205; G-protein coupledreceptor 84/G-protein coupled receptor 40 dual inhibitors such asPBI-4050; Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2)inhibitors such as KD-025; heat shock protein 47 (HSP47) smallinterfering RNA such as BMS-986263/ND-L02-s0201; Wnt pathway inhibitorsuch as SM-04646; LD4/PDE3/4 inhibitors such as Tipelukast; recombinantimmuno-modulatory domains of histidyl tRNA synthetase (HARS) such asATYR-1923; prostaglandin synthase inhibitors such as ZL-2102/SAR-191801;15-hydroxy-eicosapentaenoic acid (15-HEPE e.g. DS-102); Lysyl OxidaseLike 2 (LOXL2) inhibitors such as PAT-1251, PXS-5382/PXS-5338;phosphoinositide 3-kinases (PI3K)/mammalian target of rapamycin (mTOR)dual inhibitors such as HEC-68498; calpain inhibitors such as BLD-2660;mitogen-activated protein kinase kinase kinase (MAP3K19) inhibitors suchas MG-S-2525; chitinase inhibitors such as OATD-01; mitogen-activatedprotein kinase-activated protein kinase 2 (MAPKAPK2) inhibitors such asMMI-0100; transforming growth factor beta 1 (TGF-beta1) smallinterfering RNA such as TRK250/BNC-1021; or lysophosphatidic acidreceptor antagonists such as BMS-986278.

Anti-tussive agents are, for example, purinoceptor 3 (P2X3) receptorantagonists such as gefapixant, S-600918, BAY-1817080, or BLU-5937;neurokinin 1 (NK-1) receptor antagonist such as Orvepitant, Aprepitant;nicotinic acetylcholine receptor alpha 7 subunit stimulator such asATA-101/bradanicline; codeine, gabapentin, pregablin, or azithromycin.Anti-inflammatory agents are, for example, corticosteroids such asprednisolone or dexamethasone; cyclo-oxygenase-2 (COX2) inhibitors suchas celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib orlumiracoxib; prostaglandin E2 antagonists; leukotriene B4 antagonists;leukotriene D4 antagonists such as monteleukast; 5-lipoxygenaseinhibitors; or other nonsteroidal anti-inflammatory agents (NSAIDs) suchas aspirin, diclofenac, diflunisal, etodolac, ibuprofen or indomethacin.

Anti-atopic dermatitis agents are, for example, cyclosporin,methotrexate, mycophenolate mofetil, azathioprine, phosphodiesteraseinhibitors (e.g. apremilast, crisaborole), Janus Associated Kinase (JAK)inhibitors (e.g. tofacitinib), neutralizing antibodies againstIL-4/IL-13 (e.g. dupilamab), IL-13 (e.g. lebrikizumab, tralokinumab) andIL-31 (nemolizumab). Analgesics are, for example, of the opioid type,such as morphine, oxymorphine, levopanol, oxycodon, propoxyphene,nalmefene, fentanyl, hydrocondon, hydromorphone, meripidine, methadone,nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine, pentazocine; or of the non-opioid type, such asacetophenamine.

Anti-depressants are, for example, tricyclic anti-depressants such asamitriptyline, clomipramine, despramine, doxepin, desipramine,imipramine, nortriptyline; selective serotonin reuptake inhibitoranti-depressants (SSRIs) such as fluoxetine, paroxetine, sertraline,citalopram, escitalopram; norepinephrine reuptake inhibitoranti-depressants (SNRIs) such as maprotiline, lofepramine, mirtazapine,oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion,hydroxybuproprion, nomifensine, viloxazine; dualserotonin-norepinephrine reuptake inhibitor anti-depressants (SNRIs)such as duloxetine, venlafaxine, desvenlafaxine, levomilnacipran;atypical antidepressants such as trazodone, mirtazapine, vortioxetine,vilazodone, bupropion; or monoamine oxidase inhibitor anti-depressants(MAOIs) such as tranylcypromine, phenelzine, or isocarboxazid.

Anxiolytics are, for example, benzodiazepines such as alprazolam,bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam,flurazepam, lorazepam, oxazepam, temazepam, triazolam, or tofisopam; orthey are nonbenzodiazepine hypnotics such as eszopiclone, zaleplon,zolpidem, or zopiclone; or they are carbamates e.g. meprobamate,carisoprodol, tybamate, or lorbamate; or they are antihistamines such ashydroxyzine, chlorpheniramine or diphenhydramine.

Sedatives are, for example, barbiturate sedatives, such as amobarbital,aprobarbital, butabarbital, butabital, mephobarbital, metharbital,methohexital, pentobarbital, secobarbital, talbutal, theamylal, orthiopental; or they are non-barbiturate sedatives such as glutethimide,meprobamate, methaqualone or dichloalphenazone.

Skeletal muscle relaxants are, for example, baclofen, meprobamate,carisoprodol, cyclobenzaprine, metaxalone, methocarbamol, tizanidine,chlorzoxazone or orphenadrine.

Other suitable combination partners are inhibitors ofAcetylcholinesterase inhibitors such as donepezil; 5-HT-3 anatgonistssuch as ondansetron; metabotropic glutamate receptor antagonists;antiarrhythmics such as mexiletine or phenytoin; or NMDA receptorantagonists. Further suitable combination partners are incontinencemedications, for example, anticholinergics such as oxybutynin,tolterodine, darifenacin, fesoterodine, solifenacin or trospium; or theyare bladder muscle relaxants such as mirabegron; or they are alphablockers such as tamsulosin, alfuzosin, silodosin, doxazosin orterazosin.

The dosage for the combination partners mentioned above is usually ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by TRPA1, in particular diseases or conditions as describedhereinbefore and hereinafter.

In a further aspect this invention relates to a method for treating adisease or condition which can be influenced by the inhibition of TRPA1in a patient that includes the step of administering to the patient inneed of such treatment a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof incombination with a therapeutically effective amount of one or moreadditional therapeutic agents.

In a further aspect this invention relates to the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in combinationwith one or more additional therapeutic agents for the treatment ofdiseases or conditions which can be influenced by the inhibition ofTRPA1 in a patient in need thereof.

In yet another aspect the present invention relates to a method for thetreatment of a disease or condition mediated by TRPA1 activity in apatient that includes the step of administering to the patient,preferably a human, in need of such treatment a therapeuticallyeffective amount of a compound of the present invention in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents described in hereinbefore and hereinafter.

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts. Consequently, inanother aspect, this invention relates to a pharmaceutical compositionthat comprises a compound according to the invention and one or moreadditional therapeutic agents described hereinbefore and hereinafter,optionally together with one or more inert carriers and/or diluents.

In yet another aspect the present invention relates to the use of acompound according to the invention in a cough-measuring device.

Other features and advantages of the present invention will becomeapparent from the following more detailed examples which illustrate, byway of example, the principles of the invention.

Preparation

The compounds according to the present invention and their intermediatesmay be obtained using methods of synthesis which are known to the oneskilled in the art and described in the literature of organic synthesis.Preferably, the compounds are obtained in analogous fashion to themethods of preparation explained more fully hereinafter, in particularas described in the experimental section. In some cases, the order incarrying out the reaction steps may be varied. Variants of the reactionmethods that are known to the one skilled in the art but not describedin detail here may also be used.

The general processes for preparing the compounds according to theinvention will become apparent to the one skilled in the art studyingthe following schemes. Any functional groups in the starting materialsor intermediates may be protected using conventional protecting groups.These protecting groups may be cleaved again at a suitable stage withinthe reaction sequence using methods familiar to the one skilled in theart.

The compounds according to the invention are prepared by the methods ofsynthesis des scribed hereinafter in which the substituents of thegeneral formulae have the meanings given herein before. These methodsare intended as an illustration of the invention without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to knowncompounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.Abbreviations are as defined in the Examples section.

In scheme 1, chloromethyltetrazole is N-alkylated with an appropriateethanone derivative carrying a leaving group “LG” (e.g. Cl or Br) alphato the carbonyl group in the presence of a base (e.g. K₂CO₃) to yield amixture of two regioisomers. The undesired regioisomer (not shown) canbe removed by chromatography using an appropriate gradient. Theresulting ketone (A) can be reduced in an enantioselective fashion byusing appropriate catalytic systems using a transition metal complex (ofe.g. Ru or Ir) in combination with a chiral ligand (e.g.([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido) and ahydrogen source such as formic acid triethylamine complex to yieldalcohol (B). Final compounds (I) can be synthesized by alkylation of4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxamide (C) with intermediate(B) in presence of a base such as K₂CO₃.

In scheme 2, intermediate (C) can be synthesized from 3,4-diethyl2-aminothiophene-3,4-dicarboxylate (CAS: 104680-25-3) via condensationwith formamidine, e.g. using formamidinium acetate, to provide (D), andsubsequent amide formation, e.g. with ammonia in presence of CaCl₂).

EXAMPLES Preparation

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis forexample using methods described in “Comprehensive OrganicTransformations”, 2nd Edition, Richard C. Larock, John Wiley & Sons,2010, and “March's Advanced Organic Chemistry”, 7th Edition, Michael B.Smith, John Wiley & Sons, 2013. Preferably the compounds are obtainedanalogously to the methods of preparation explained more fullyhereinafter, in particular as described in the experimental section. Insome cases the sequence adopted in carrying out the reaction schemes maybe varied. Variants of these reactions that are known to the skilledartisan but are not described in detail herein may also be used. Thegeneral processes for preparing the compounds according to the inventionwill become apparent to the skilled man on studying the schemes thatfollow. Starting compounds are commercially available or may be preparedby methods that are described in the literature or herein, or may beprepared in an analogous or similar manner Before the reaction iscarried out, any corresponding functional groups in the startingcompounds may be protected using conventional protecting groups. Theseprotecting groups may be cleaved again at a suitable stage within thereaction sequence using methods familiar to the skilled man anddescribed in the literature for example in “Protecting Groups”, 3rdEdition, Philip J. Kocienski, Thieme, 2005, and “Protective Groups inOrganic Synthesis”, 4th Edition, Peter G. M. Wuts, Theodora W. Greene,John Wiley & Sons, 2006. The terms “ambient temperature” and “roomtemperature” are used interchangeably and designate a temperature ofabout 20° C., e.g. between 19 and 24° C.

Abbreviations: ACN acetonitrile Aq. Aqueous ° C. Degree celsius CDICarbonyl diimidazole CyH/CH cyclohexane conc. Concentrated DCM dichloromethane DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMFN,N-dimethylformamide DMSO dimethyl sulfoxide ESI-MS Electrosprayionisation mass spectrometry EtOAc ethyl acetate EtOH ethanol ex exampleeq equivalent FA formic acid h hour HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HCl Hydrochloric acid HPLC High performanceliquid chromatography Int. Intermediate K₂CO₃ potassium carbonateK(OtBu) Potassium tert. butoxide L liter LiOH*H₂O Lithium hydroxidemonohydrate M molar MeOH methanol MgSO₄ magnesium sulphate min minute mLmilliliter MTBE tert-butylmethylether NaOEt Sodium ethanolate NH₃ammonia PMB Para-methoxy benzyl Prep. preparative RP Reversed phase RTroom temperature (about 20° C.) sat. saturated TBTU Benzotriazolyltetramethyluronium tetrafluoroborate TEA triethylamine TFAtrifluoroacetic acid TFAA trifluoroacetic anhydride THF TetrahydrofuranTMS-Cl Trimethylsilyl chloride

Preparation of Intermediates Intermediate I

Intermediate I.1 (General Procedure)

2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethan-1-one

To 1.00 g (8.44 mmol) 5-(chloromethyl)-2H-1,2,3,4-tetrazole and 2.17 g(9.28 mmol) 4-chlorophenacyl bromide in 15 mL DMA are added 1.63 g (11.8mmol) K₂CO₃ under stirring at RT. The reaction mixture is stirred for 30min at RT and subsequently filtered. The filtrate is diluted with waterand sat. aq. NaCl-solution and is extracted with EtOAc three times. Thecombined organic phases are washed with water, dried over Na₂SO₄,filtered over activated charcoal and the solvent is removed underreduced pressure. The residue is purified by column chromatography(silica gel; CH/EtOAc, 80/20 to 50/50 gradient) to provide the product.

C₁₀H₈Cl₂N₄O (M=271.1 g/mol)

ESI-MS: 271 [M+H]⁺

R_(t) (HPLC): 1.01 min (method B)

The following compounds are prepared using procedures analogous to thosedescribed for intermediate I.1 using appropriate starting materials. Asis appreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions.

¹H NMR (300 MHz, DMSO-d₆) Reaction δ ppm or conditions HPLC re-(deviation tention from gen- time [min] eral proce- Int. Startingmaterials Structure ESI-MS (method) dure) I.2 IV.5

5.10 (s, 2H), 6.59 (dd, J = 6.4, 0.8 Hz), 6.75 (m, 2H), 7.83 (d, J = 8.7Hz), 8.03 (dd, J = 8.7, 1.9 Hz), 8.37 (d, J = 1.9 Hz, 1H) I.3 IV.6

295 [M + H]⁺ 0.56 (A) ACN, 10 min I.4

293 [M + H]⁺ 1.12 (B) Starting materials 1:1 I.5

311 [M + H]⁺ 1.23 (B) 2 eq base I.6

311/313 [M + H]⁺ 1.31 (B) I.7

315/317 [M + H]⁺ 1.00 (H) Stirred for 1 h; I.8

311 [M + H]⁺ 1.08 (H) Starting materials 1:1 I.9

277 [M + H]⁺ 1.26 (B) 2 eq base, starting materials 1:1 Stirred for 15min I.10 IV.7

295 [M + H]⁺ 1.02 (B) Starting materials 1:1 I.11

277 [M + H]⁺ 1.01 (H) I.12

251 [M + H]⁺ 0.95 (H) I.13 IV.8

268 [M + H]⁺ 0.47 (G) ACN, stirred for 1.5 h, puri- fied by prep. HPLCI.14

267 [M + H]⁺ 0.75 (C) *see below table I.15 IV.1

— 5.03 (s, 2H), 6.59 (s, 2H), 8.08 (m, 2H), 8.18 (m, 1H). Stirred for 1h I.16 IV.2

— 5.10 (s, 2H), 6.59 (s, 2H), 8.04 (m, 1H), 8.17 (m, 1H) 8.25 (m,Stirred for 1 h 1H) I.17 IV.3

— 5.10 (s, 2H), 6.59 (s, 2H), 8.09 (m, 1H), 8.15 (m, 1H), 8.27 (m,Stirred for 1 h 2H) I.18 IV.4

— 5.11 (s, 2H), 6.79 m, 2H), 8.08 (m, 2H), 8.27 (m, 1H), 8.54 (m, 1H)Stirred for 2 h *p-methoxyphenacyl bromide (1.05 eq.) is slowly added toa stirred solution of chloromethyltetrazole and K₂CO₃ (1.4 eq) in DMA at18° C.; mixture is stirred at RT for 1.5 h; purification via reversedphase HPLC (ACN/H₂O gradient, 0.1% TFA).

Intermediate II

Intermediate II.1 (General Procedure)

(1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethan-1-ol

1.30 g (4.80 mmol)1-(4-chlorophenyl)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]ethan-1-one(intermediate I.1) is dissolved in 20 mL ACN under inert atmosphere. 12mg (0.02 mmol)Chloro([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) (CAS 174813-81-1) are added followed by dropwise addition of 0.72mL (1.73 mmol) formic acid triethylamine complex (5:2). After stirringat RT for 3 h, the solvent is removed under reduced pressure. To theremaining crude mixture is added water and this mixture is extractedwith EtOAc. The organic layers are combined, dried over Na₂SO₄,filtered, treated with activated charcoal, filtered and the solvent isremoved under reduced pressure to provide intermediate II. 1.

C₁₀H₁₀Cl₂N₄O (M=273.1 g/mol)

ESI-MS: 273 [M+H]⁺

R_(t) (HPLC): 0.96 min (method B)

The following compounds are prepared using procedures analogous to thosedescribed for intermediate II.1 using appropriate starting materials. Asis appreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions.

HPLC retention Starting time [min] Int. materials Structure ESI-MS(method) II.2 I.2

341 [M + HCO₂]⁻ 2.63 (J) II.3 I.3

297 [M + H]⁺ 0.52 (A) II.4 I.4

295 [M + H]⁺ 1.10 (B) II.5 I.5

313 [M + H]⁺ 1.17 (B) II.6 I.6

313/315 [M + H]⁺ 1.26 (B) II.7 I.7

317/319 [M + H]⁺ 1.14 (B) II.8 I.8

313 [M + H]⁺ 1.03 (B) II.9 I.9

279 [M + H]⁺ 1.14 (B) II.10 I.10

297 [M + H]⁺ 0.97 (B) II.11 I.11

279 [M + H]⁺ 0.97 (H) II.12 I.12

253 [M + H]⁺ 0.48 (A) II.13 I.13

270 [M + H]⁺ 0.41 (A) II.14 I.14

269 [M + H]⁺ 0.45 (G) II.15 I.15

359 [M + HCO₂]⁻ 3.05 (N) II.16 I.16

375 [M + HCO₂]⁻ 3.47 (O) II.17 I.17

375 [M + HCO₂]⁻ 4.21 (O) II.18 I.18

348 [M + HCO₂]⁻ 2.56 (N)

Intermediate III

Intermediate III.1 (General Procedure)

1-(5,6-difluoro-1-benzofuran-2-yl)ethan-1-one

5.00 g (31.6 mmol) 4,5-difluoro-2-hydroxybenzaldehyde in 50 mL acetoneis treated with 6.99 g (50.6 mmol) potassium carbonate under argon at 0°C. After additional stirring for 10 min at 0° C., 3.78 mL (47.4 mmol)chloroacetone are added dropwise and the reaction mixture is stirred at70° C. for 3 h. The reaction mixture is cooled to RT and concentrated.The crude is extracted with EtOAc/water and the organic phase isconcentrated under reduced pressure to provide intermediate III.1.

C₁₀H₆F₂O₂ (M=196.2 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.56 (s, 3H), 7.89 (m, 1H), 7.92 (m,1H), 8.01 (m, 1H)

The following compounds are prepared using procedures analogous to thosedescribed for intermediate III.1 using appropriate starting materials.As is appreciated by those skilled in the art, these analogous examplesmay involve variations in general reaction conditions.

¹H NMR (300 MHz, DMSO-d₆) Reaction δ ppm or conditions HPLC re-(deviation tention time from gen- Starting [min] eral proce- Int.materials Structure ESI-MS (method) dure) III.2

— 2.57 (s, 3H), 7.90 (m, 2H), 8.16 (dd, J = 6.0, 1.0 Hz, 1H) III.3

— 2.56 (s, 3H), 7.88 (d, J = 1.0 Hz, 1H), 8.01 (dd, J = 9.4, 1.0 Hz,1H), 8.12 (d, J = 7.6 Hz, 1H) Heated to 90° C. for 1 h III.4

179 [M + H]⁺ 0.50 (A) Stirred at 90° C. for 1 h III.5

179 [M + H]⁺ 0.95 (B) 1.1 eq chloro- acetone; III.6

— 1.34 (t, J = 7.1 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 7.55 (m, 1H), 7.77(m, 2H), 8.10 (m, 1H) DMF, 1.0 eq bromo acetic acid ethyl ester, stirredat 90° C. overnight

III.7

— 1.35 (t, J = 7.1 Hz, 3 H), 4.38 (q, J = 7.1 Hz, 2 H), 7.68 (dd, J =8.8, 2.1 Hz, 1 H), 7.72- Solvent: DMF; 1.0 eq bromo- acetic acid ethylester instead of chloroacetone; 7.79 (m, 2 1.5 eq. H), 8.04 K₂CO₃, (dd,J = 2.1, stirred at 0.6 Hz, 1 H) 92° C. over- night

Intermediate IV

Intermediate IV.1 (General Procedure)

2-bromo-1-(5,6-difluoro-1-benzofuran-2-yl)ethan-1-one

500 mg (2.55 mmol) 1-(5,6-difluoro-1-benzofuran-2-yl)ethan-1-one(III. 1) in 6 mL THF is treated dropwise with 1.23 g (2.55 mmol)tetrabutylammonium tribromide in 300 μL MeOH and 3 mL THF. The reactionmixture is stirred at RT for 2 h. The reaction mixture is concentratedunder reduced pressure and the residue is extracted with EtOAc/water.The organic phase is concentrated under reduced pressure and the crudematerial is purified by column chromatography (silica gel;Hexanes/EtOAc, 9/1 to 7/3 gradient).

C₁₀H₅BrF₂O₂ (M=275.0 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 4.83 (s, 2H), 7.98-8.12 (m, 3H)

The following compounds are prepared using procedures analogous to thosedescribed for intermediate IV.1 using appropriate starting materials. Asis appreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions

¹H NMR (300 MHz, DMSO-d₆) δ ppm or HPLC retention time Starting [min]Int. materials Structure ESI-MS (method) IV.2 III.1

— 4.84 (s, 2H), 7.97 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 8.20(dd, J = 6.0, 0.9 Hz, 1H) IV.3 III.3

— 4.83 (s, 2H), 8.03- 8.21 (m, 3H) IV.4 VIII

— 5.05 (s, 2H), 7.96- 8.10 (m, 2H), 8.17- 8.27 (m, 1H), 8.34- 8.53 (m,1H) IV.5 XI

— 4.99 (s, 2H), 6.53 (dd, J = 6.4, 0.9 Hz, 1H), 7.75 (d, J = 8.7, 1H),7.88-8.03 (m, 1H), 8.31 (dd, J = 1.9, 0.6 Hz, 1H) IV.6 III.4

257/259 [M + H]⁺ 0.58 (A) IV.7 III.5

257/259 [M + H]⁺ 1.03 (B) IV.8*

228/230 [M − H]⁻ 0.75 (I) *The reaction is performed with bromine (13.6eq) at RT for 2 h in dioxane/diethyl ether and quenched with sodiumthiosulfate solution.

Intermediate V Ethyl 6-acetyl-1-benzofuran-2-carboxylate

To 1.00 g (3.72 mmol) ethyl 6-bromo-1-benzofuran-2-carboxylate (III.6)in 12.5 mL DMF is added 616 mg (4.46 mmol) potassium carbonate. Themixture is purged with argon and 92 mg (0.22 mmol)1,3-Bis(diphenylphosphino)propane, 250 mg (0.11 mmol) palladium(II)acetate and 670 mg (9.29 mmol) ethyl vinyl ether are added. The reactionmixture is stirred at 80° C. for 18 h, then cooled to RT and the pH isadjusted to pH=1 by addition of 1M aq. HCl. The crude product wasextracted with EtOAc, concentrated under reduced pressure, and purifiedby column chromatography (silica gel; Hexane/EtOAc 7/3).

C₁₃H₁₂O₄ (M=232.2 g/mol)

ESI-MS: 233 [M+H]⁺

R_(t) (HPLC): 1.38 min (method Q)

Intermediate VI 6-acetyl-1-benzofuran-2-carboxylic Acid

To 6.60 g (28.4 mmol) ethyl 6-acetyl-1-benzofuran-2-carboxylate (y) in66 mL THF and 33 mL water is added 3.3 mL ethanol and 1.43 g (34.1 mmol)LiOH monohydrate. The reaction mixture is stirred at RT for 1 h andconcentrated to dryness under reduced pressure to provide theintermediate.

C₁₁H₈O₄ (M=204.2 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.67 (s, 3H), 7.73 (m, 1H), 7.99-7.85(m, 2H), 8.32 (m, 1H), 13.30-14.50 (br s, 1H)

Intermediate VII 6-acetyl-1-benzofuran-2-carboxamide

To 1.00 g (4.90 mmol) 6-acetyl-1-benzofuran-2-carboxylic acid (VI) in 10mL DCM is added 932 mg (7.34 mmol) oxalyl chloride and 1 drop of DMF at0° C. The reaction mixture is stirred for 2 h at RT and concentrated todryness. The residue is dissolved in 10 mL THF, cooled to 0° C. and 15mL 25% aqueous ammonia is added. The reaction mixture is stirred at RTfor 16 h and concentrated to dryness under reduced pressure to providethe intermediate.

C₁₁H₉NO₃ (M=203.2 g/mol)

ESI-MS: 204 [M+H]⁺

R_(t) (HPLC): 0.96 min (method Q)

Intermediate VIII 6-acetyl-1-benzofuran-2-carbonitrile

To 0.90 g (4.43 mmol) 6-acetyl-1-benzofuran-2-carboxamide (VII) and 1.4mL (9.88 mmol) TEA in 12 mL THF are added 1.1 mL (7.77 mmol) TFAAdropwise under stirring at 0° C. The reaction mixture is stirred at 0°C. for 1 h, quenched with water and extracted with EtOAc three times.The combined organic layers are washed with sat. NaHCO₃ and brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to providethe intermediate.

C₁₁H₇NO₂ (M=185.2 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.68 (s, 3H), 7.92-8.05 (m, 2H), 8.21(m, 1H), 8.37 (m, 1H).

Intermediate IX 5-bromo-1-benzofuran-2-carboxylic Acid

To 6.58 g (24.4 mmol) ethyl 5-bromo-1-benzofuran-2-carboxylate (III.7)in 3 mL EtOH, 66 ml THF and 33 mL water are added 1.23 g (29.3 mmol)LiOH*H₂O at 0° C. The reaction mixture is stirred at RT for 2 h andsubsequently concentrated under reduced pressure. The residue isacidified with 1M HCl to pH 5 and the resulting precipitate is filteredoff and dried to provide intermediate V.

C₉H₅BrO₃ (M=241.0 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 7.59-7.76 (m, 3H), 8.02 (d, J=2.0 Hz,1H), 13.5-14.2 (br s, 1H).

Intermediate X 5-bromo-2-fluoro-1-benzofuran

5.00 g (20.7 mmol) 5-bromo-1-benzofuran-2-carboxylic acid (IX), 14.70 g(41.5 mmol) Selectflour and 4.82 g (83.0 mmol) potassium fluoride in 185ml DCE and 95 ml water are stirred in a sealed tube at 70° C. for 20 h.Subsequently, the reaction mixture is extracted with DCM/water. Theorganic layer is washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue is purified by column chromatography(silica gel, DCM).

C₈H₄BrFO (M=215.0 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 6.36 (dd, J=6.4, 0.9 Hz, 1H), 7.47 (dd,J=8.7, 2.1 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H)

Intermediate XI 1-(2-fluoro-1-benzofuran-5-yl)ethan-1-one

To 218 mg (1.0 mmol) 5-bromo-2-fluoro-1-benzofuran (X) in 3 mL DMF and0.3 mL water are added 168 mg (1.2 mmol) potassium carbonate understirring at RT. The mixture is purged with argon followed by addition of25 mg (0.1 mmol) 1,3-bis(diphenylphosphino)propane, dppp, 7 mgpalladium(II) acetate and 183 mg (2.5 mmol) ethyl vinyl ether. Thereaction mixture is stirred at 80° C. overnight, then cooled to RT andtreated with aq. 1M HCl (20 mL). After stirring at RT for 30 min, themixture is extracted with EtOAc and the combined organic layers areconcentrated under reduced pressure. The crude product is purified bycolumn chromatography (silica gel; EtOAc/hexane, gradient).

C₁₀H₇FO₂ (M=178.2 g/mol)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.63 (s, 3H), 6.49 (dd, J=6.4, 0.8 Hz,1H), 7.70 (dt, J=8.7, 0.8 Hz, 1H), 7.93 (dd, J=8.7, 1.9 Hz, 1H), 8.25(dd, J=1.9, 0.6 Hz, 1H)

Intermediate XII Ethyl 4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxylate

A mixture of 13.9 g (57.14 mmol) diethyl2-aminothiophene-3,4-dicarboxylate and 24.4 g (234.26 mmol)formamidinium acetate in 100 mL ethanol are refluxed under stirring for18 h. After cooling to RT, the reaction mixture is concentrated underreduced pressure, treated with water, and extracted with EtOAc threetimes. Combined organic layers are treated with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue is treated with waterand the precipitate is filtered off and dried to provide intermediateXII.

C₉H₈N₂O₃S (M=224.24 g/mol)

ESI-MS: 225 [M+H]⁺

R_(t) (HPLC): 0.70 min (method H)

Intermediate XIII 4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxamide

To 490 mg (2.19 mmol) ethyl4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxylate (intermediate XII) in3.0 mL EtOH are added 728 mg (6.56 mmol) CaCl₂ and 2.81 mL (19.67 mmol)ammonia in MeOH (7 M). The mixture is stirred at 60° C. for 3 h, treatedwith additional ammonia in MeOH (3 mL, 21.0 mmol) and stirred at 60° C.for 15 h. Subsequently, the mixture is concentrated under reducedpressure, 25 mL water are added, and the resulting precipitate isfiltered off, washed with water, and dried to provide intermediate XIII

C₇H₅N₃O₂S (M=195.2 g/mol)

ESI-MS: 196 [M+H]⁺

R_(t) (HPLC): 0.24 min (method G)

Preparation of Final Compounds Example 1 (General Procedure)3-({2-[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxamide

To 100 mg (0.51 mmol) 4-oxo-3H,4H-thieno[2,3-d]pyrimidine-5-carboxamide(intermediate XIII) in 4 mL DMF are added 154 mg (0.56 mmol)(1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethan-1-ol(intermediate II.1) and 106 mg (0.77 mmol) K₂CO₃ and the mixture isstirred at RT overnight. The mixture is purified by reversed phase HPLC(ACN/H₂O gradient, 0.1% NH₃) to yield the desired product.

C₁₆H₁₆ClN₇O₄ (M=431.9 g/mol)

ESI-MS: 432 [M+H]⁺

R_(t) (HPLC): 0.82 min (method C)

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 4.73-4.84 (m, 2H), 5.11 (dd, J=7.4, 5.3Hz, 1H), 5.58 (s, 2H), 5.91 (br s, 1H), 7.31-7.39 (m, 4H), 7.65 (br d,J=1.5 Hz, 1H), 8.39 (s, 1H), 8.77 (s, 1H), 9.79 (br d, J=1.7 Hz, 1H).

The following compounds are prepared using procedures analogous to thosedescribed for example 1 using appropriate starting materials. As isappreciated by those skilled in the art, these analogous examples mayinvolve variations in general reaction conditions.

Starting Reaction Ex. materials Structure conditions 2 XIII + II.5

DMA, 1.0 eq II.5, 3.0 eq base, RT, overnight 3 XIII + II.8

DMA, 0.6 eq II.8, 2.1 eq base, RT, overnight 4 XIII + II.2

DMF, 1.0 eq II.2, 1.5 eq base, RT, overnight 5 XIII + II.4

DMF, 1.0 eq II.4, 3.3 eq base, 50° C., overnight 6 XIII + II.10

DMA, 1.1 eq II.10, 2.0 eq base, RT, overnight 7 XIII + II.6

DMF, 1.1 eq II.6, 3.0 eq base, RT, overnight 8 XIII + II.17

DMA, 1.0 eq. II.17, 3.0 eq base, RT, overnight 9 XIII + II.9

DMA, 1.0 eq Int II.1, 3.0 eq base, 18 h, RT 10 XIII + II.12

DMA, 1.1 eq II.12, 2.1 eq base, RT, overnight 11 XIII + II.11

DMA, 1.1 eq II.11, 2.1 eq base, RT, overnight 12 XIII + II.7

DMF, 1.0 eq II.7, 3.0 eq base, RT, overnight 13 XIII + II.15

DMF, 1.0 eq II.15, 3.3 eq base, 50° C., 5 h 14 XIII + II.3

DMF, 1.0 eq II.3, 1.5 eq base, RT, overnight 15 XIII + II.16

DMA, 1.0 eq II.16, 3.0 eq base, RT, overnight 16 XIII + II.18

DMF, 1.0 eq II.18, 1.5 eq base, RT, overnight 17 XIII + II.14

DMA, 1.1 eq II.14, 2.0 eq base, RT, overnight 18 XIII + II.13

DMA, 1.1 eq II.13, 3.0 eq base, RT, overnight

Analytical data for the compounds described in the table above:

HPLC retention time [min] Ex. ESI-MS (method) ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2 472 0.62 4.87-5.02 (m, 2 H), 5.44 (dd, J = 8.1, 4.6 Hz, 1 H),[M + H]⁺ (E) 5.60 (s, 2 H), 7.20 (td, J = 9.0, 2.5 Hz, 1 H), 7.28 (s, 1H), 7.65 (br d, J = 1.8 Hz, 1 H), 7.75 (dd, J = 8.7, 5.3 Hz, 1 H), 7.82(dd, J = 9.4, 2.4 Hz, 1 H), 8.38 (s, 1 H), 8.76 (s, 1 H), 9.77 (br d, J= 1.9 Hz, 1 H) 3 472 0.71 4.97-5.09 (m, 2 H), 5.27 (dd, J = 7.5, 4.9 Hz,1 H), [M + H]⁺ (E) 5.58 (s, 2 H), 6.27 (hr s, 1 H), 6.80 (s, 1 H), 7.30(dd, J = 8.7, 2.3 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 2.2Hz, 2 H), 8.38 (s, 1 H), 8.74 (s, 1 H), 9.76 (br d, J = 1.8 Hz, 1 H) 4456 0.65 4.79-4.83 (m, 2 H), 5.18 (t, J = 6.4 Hz, 1 H), 5.59 [M + H]⁺(D) (s, 2 H), 5.87 (hr s, 1 H), 6.28 (dd, J = 6.4, 0.7 Hz, 1 H), 7.27(dd, J = 8.6, 1.7 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 1 H), 7.58 (br d, J =1.7 Hz, 1 H), 7.65 (br d, J = 1.7 Hz, 1 H) 8.39 (s, 1 H), 8.78 (s, 1 H),9.78 (br d, J = 1.9 Hz, 1 H) 5 454 0.45 4.85-5.03 (m, 2 H), 5.46 (dd, J= 8.1, 4.5 Hz, 1 H), [M + H]⁺ (A) 5.61 (s, 2 H), 6.44 (hr s, 1 H),7.24-7.38 (m, 3 H), 7.65 (br d, J = 1.7 Hz, 1 H), 7.70-7.76 (m, 1 H),7.87- 7.93 (m, 1 H), 8.39 (s, 1 H), 8.74-8.81 (m, 1 H), 9.78 (br d, J =1.4 Hz, 1 H) 6 456 0.63 4.97-5.09 (m, 2 H), 5.23-5.29 (m, 1 H), 5.58 (s,2 [M + H]⁺ (E) H), 6.27 (d, J = 5.8 Hz, 1 H), 6.80-6.82 (m, 1 H), 7.11(td, J = 9.2, 2.7 Hz, 1 H), 7.37 (dd, J = 8.9, 2.7 Hz, 1 H), 7.55 (dd, J= 8.9, 4.3 Hz, 1 H), 7.64 (br d, J = 1.8 Hz, 1 H), 8.38 (s, 1 H), 8.74(s, 1 H), 9.76 (br d, J = 1.9 Hz, 1 H) 7 472 1.14 4.79-4.99 (m, 2 H),5.28-5.33 (m, 1 H), 5.60 (s, 2 [M + H]⁺ (B) H), 6.55 (hr s, 1 H), 7.07(d, J = 0.9 Hz, 1 H), 7.63 (hr d, J = 1.5 Hz, 1 H), 8.38 (s, 1 H), 8.77(s, 1 H), 9.77 (br d, J = 1.6 Hz, 1H) 8 490 0.66 4.96-5.08 (m, 2 H),5.23-5.29 (m, 1), 5.57 (s, 1 H), [M + H]⁺ (D) 5.89-6.62 (hr s, 1H), 6.81(s, 1 H), 7.64 (br d, J = 1.8 Hz, 1 H), 7.75-7.81 (m, 2 H), 8.38 (s, 1H), 8.72 (s, 1 H), 9.76 (br d, J = 1.8 Hz, 1 H) 9 438 0.56 4.97-5.09 (m,2 H), 5.27 (dd, J = 7.9, 4.8 Hz, 1 H), [M + H]⁺ (D) 5.59 (s, 2 H),5.96-6.54 (hr s, 1H), 6.81 (m, 1 H), 7.18-7.24 (m, 1 H), 7.25-7.31 (m, 1H), 7.51-7.59 (m, 2 H), 7.64 (br d, J = 1.7 Hz, 1 H), 8.38 (s, 1 H),8.75 (s, 1 H), 9.77 (br d, J = 1.9 Hz, 1 H) 10 412 0.62 2.25 (s, 3 H),4.74 (d, J = 6.5 Hz, 2 H), 5.05 (t, J = 6.5 [M + H]⁺ (E) Hz, 1 H), 5.59(s, 2 H), 7.06-7.11 (m, 2 H), 7.19- 7.23 (m, 2 H), 7.65 (br d, J = 1.5Hz, 1 H), 8.39 (s, 1 H), 8.77 (s, 1 H), 9.79 (br d, J = 1.4 Hz, 1 H) 11438 0.63 4.78-4.92 (m, 2 H), 5.26-5.31 (m, 1 H), 5.60 (s, 2 [M + H]⁺ (E)H), 6.83 (dd, J = 3.9, 0.8 Hz, 1 H), 6.91 (d, J = 3.9 Hz,1 H), 7.64 (brd, J = 1.1 Hz, 1 H), 8.38 (s, 1 H), 8.78 (s, 1 H), 9.76-9.79 (m, 1 H) 12475/477 0.64 4.73-4.83 (m, 2 H), 5.09 (dt, J = 7.6, 5.0 Hz, 1 H), [M +H]⁺ (D) 5.59 (s, 2 H), 5.91 (d, J = 4.8 Hz, 1 H), 7.28-7.33 (m, 2 H),7.46-7.51 (m, 2 H), 7.65 (br d, J = 1.7 Hz, 1 H), 8.39 (s, 1 H), 8.77(s, 1 H), 9.78 (br d, J = 1.8 Hz, 1 H) 13 474 0.97 4.96-5.08 (m, 2 H),5.25 (dd, J = 7.4, 5.0 Hz, 1 H), [M + H]⁺ (B) 5.57 (s, 2 H), 6.27 (hr s,1H), 6.81 (s, 1 H), 7.57- 7.66 (m, 2 H), 7.78 (dd, J = 10.5, 6.6 Hz, 1H), 8.38 (s, 1 H), 8.72 (s, 1 H), 9.75 (br d, J = 1.8 Hz, 1 H) 14 4560.56 4.99-5.12 (m, 2 H), 5.27-5.34 (m, 1 H), 5.58 (s, 2 [M + H]⁺ (D) H),6.32 (d, J = 5.7 Hz, 1 H), 6.90-6.92 (m, 1 H), 7.14-7.24 (m, 2 H),7.36-7.42 (m, 1 H), 7.63 (br d, J = 1.8 Hz, 1 H), 8.38 (s, 1 H), 8.74(s, 1 H), 9.76 (hr d, J = 1.8 Hz, 1 H) 15 490 0.70 4.96-5.08 (m, 2 H),5.24-5.29 (m, 1 H), 5.57 (s, 2 [M + H]⁺ (D) H), 6.32 (hr s, 1 H), 6.83(m, 1 H), 7.59 (d, J = 9.1 Hz, 1 H), 7.63 (br d, J = 1.9 Hz, 1 H), 7.89(dd, J = 6.0, 0.7 Hz, 1 H), 8.38 (s, 1 H), 8.72 (s, 1 H), 9.76 (hr d, J= 1.9 Hz, 1 H) 16 463 0.81 4.82-4.92 (m, 2 H), 5.28 (dd, J = 7 .3, 5.3Hz, 1 H), [M + H]⁺ (H) 5.58 (s, 2 H), 7.42 (dd, J = 8.2, 1.1 Hz, 1 H),7.63- 7.66 (m, 1 H), 7.72-7.77 (m, 2 H), 8.05 (d, J = 0.8 Hz, 1 H), 8.39(s, 1 H), 8.75 (s, 1 H), 9.76-9.80 (m, 1 H) 17 428 0.38 3.71 (s, 3 H),4.68-4.79 (m, 2 H), 5.01-5.07 (m, 1 [M + H]⁺ (A) H), 5.59 (s, 2 H), 5.71(hr s, 1 H), 6.83-6.87 (m, 2 H), 7.24-7.29 (m, 2 H), 7.65 (br d, J = 1.8Hz, 1 H), 8.39 (s, 1 H), 8.78 (s, 1 H), 9.79 (br d, J = 1.8 Hz, 1 H) 18429 0.40 4.84-5.03 (m, 2 H), 5.42-5.48 (m, 1 H), 5.60 (s, 2 [M + H]⁺ (K)H), 6.69 (d, J = 5.3 Hz, 1 H), 7.15 (d, J = 3.9 Hz, 1 H), 7.64 (br d, J= 1.5 Hz, 1 H), 7.80 (d, J = 3.8 Hz, 1 H), 8.38 (s, 1 H), 8.77 (s, 1 H),9.77 (br d, J = 1.5 Hz, 1 H)

Analytical HPLC Methods Method A

time Vol % water Vol % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.00 991 1.6 0.02 99 1 1.6 1.00 0 100 1.6 1.10 0 100 1.6 Analytical column:XBridge BEH (Waters) C18_2.1 × 30 mm_1.7 μm; column temperature: 60° C.

Method B

time Vol % water Vol % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: Stable Bond (Agilent) C18_3.0 × 30 mm_1.8 μm; columntemperature: 60° C.

Method C

time Vol % water Vol % Flow (min) (incl. 0.1% NH3) ACN [mL/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: Xbridge (Waters) C18_3.0 × 30 mm_2.5 μm; columntemperature: 60° C.

Method D

time Vol. % water Vol. % Flow (min) (incl. 0.1 % NH₄OH) ACN [mL/min]0.00 95 5 1.5 1.30 0 100 1.5 1.50 0 100 1.5 1.60 95 5 1.5 Analyticalcolumn: XBridge C18_3.0 × 30 mm_2.5 μm (Waters); column temperature: 60°C.

Method E

time Vol % water Vol % ACN Flow (min) (incl. 0.1% TFA) 0.08% TFA[mL/min] 0.00 95 5 1.5 1.30 0 100 1.5 1.50 0 100 1.5 1.60 95 5 1.5Analytical column: Sunfire (Waters); C18_3.0 × 30 mm_2.5 μm; columntemperature: 60° C.

Method F

time Vol % water Vol % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.00 955 1.3 0.02 95 5 1.3 1.00 0 100 1.3 1.30 0 100 1.3 Analytical column:XBridge BEH (Waters) C18_2.1 × 30 mm_2.5 μm; column temperature: 60° C.

Method G

time Vol.% water Vol. % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.00 991 1.6 0.02 99 1 1.6 1.0 0 100 1.6 1.1 0 100 1.6 Analytical column:Zorbax StableBond C18 (Agilent) 1.8 μm; 2.1 × 30 mm; column temnerature:60° C.

Method H

time Vol % water Vol % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: Sunfire (Waters) 2.5 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method I

time Vol. % water Vol. % Flow (min) (incl. 0.1% TFA) ACN [mL/min] 0.0095 5 1.5 1.30 0 100 1.5 1.50 0 100 1.5 Analytical column: Sunfire C18(Waters) 2.5 μm; 3.0 × 30 mm; column temperature: 60° C.

Method J

time Vol.% water Vol % ACN Flow (min) (incl. 0.1% FA) (incl. 0.1% FA)[mL/min] 0.00 60 40 0.5 6.00 40 60 0.5 6.8 40 60 0.5 7.00 10 90 0.5 8.1010 90 0.5 8.50 60 40 0.5 10 60 40 0.5 Analytical column: Acquity UPLCBEH ; C8_2.1 × 150 mm_1.7 μm; column temperature: 55° C.

Method K

time Vol % water Vol % Flow (min) (incl. 0.1% NH3) ACN [mL/min] 0.00 955 1.3 0.02 95 5 1.3 1.00 0 100 1.3 1.30 0 100 1.3 Analytical column:XBridge BEH Phenyl (Waters) 2.1 × 30 mm_1.7 μm; column temperature: 60°C.

The invention claimed is:
 1. A compound according to formula (I)

wherein A is selected from the group consisting of phenyl, thienophenyl,benzothiophenyl and benzofuranyl, unsubstituted or substituted with oneor two members of the group R¹ selected from —CN, halogen, C₁₋₄-alkyl,O—C₁₋₄-alkyl, C₁₋₄-fluoroalkyl, O—C₁₋₄-fluoroalkyl, C₃₋₄-cycloalkyl,O—C₃₋₄-cycloalkyl, C₃₋₄-cyclofluoroalkyl and O—C₃₋₄-cyclofluoroalkyl; ora salt thereof.
 2. The compound of formula (I) according to claim 1,wherein R¹ is selected from H₃C—O, NC—, Br, Cl, F and H₃C.
 3. Thecompound of formula (I) according to claim 1, wherein A is selected fromthe group consisting of

unsubstituted or substituted with one or two members of the group R¹. 4.The compound of formula (I) according to claim 1, wherein A is selectedfrom the group consisting of


5. The compound of formula (I) according to claim 1, selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 1, in the form of a pharmaceutically acceptable salt.
 7. Apharmaceutical composition comprising at least one compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.
 8. A method forthe treatment of inflammatory airway diseases, fibrotic diseases orcough, comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 9. A Themethod according to claim 8, for the treatment of idiopathic lungdisease (IPF) or cough.
 10. A compound having the following formula:

or a pharmaceutically acceptable salt thereof.
 11. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 12. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 14. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 15. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 16. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 17. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 18. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 19. A compound having thefollowing formula:

or a pharmaceutically acceptable salt thereof.
 20. A compound having thefollowing formula:


21. A compound having the following formula:


22. A compound having the following formula:


23. A compound having the following formula:


24. A compound having the following formula:


25. A compound having the following formula:


26. A compound having the following formula:


27. A compound having the following formula:


28. A compound having the following formula:


29. A compound having the following formula: